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A proposal for the molecular basis of μ and δ opiate receptor differentiation based on modeling of two types of cyclic enkephalins and a narcotic alkaloid

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Summary

The molecular basis underlying the divergent receptor selectivity of two cyclic opioid peptides Tyr-c[N δ-d-Orn2-Gly-Phe-Leu-] (c-ORN) and [d-Pen2, l-Cys5]-enkephalinamide (c-PEN) was investigated using a molecular modeling approach. Ring closure and conformational searching procedures were used to determine low-energy cyclic backbone conformers. Following reinsertion of amino acid side chains, the narcotic alkaloid 7α-[(1R)-1-methyl-1-hydroxy-3-phenylpropyl]-6,14-endoethenotetrahydro oripavine (PEO) was used as a flexible template for bimolecular superpositions with each of the determined peptide ring conformers using the coplanarity and cocentricity of the phenolic rings as the minimum constraint. A vector space of PEO, accounting for all possible orientations for the C21-aromatic ring of PEO served as a geometrical locus for the aromatic ring of the Phe4 residue in the opioid peptides. Although a vast number of polypeptide conformations satisfied the criteria of the opiate pharmacophore, they could be grouped into three classes differing in magnitude and sign of the torsional angle values of the tyrosyl side chain. Only class III conformers for both c-ORN and c-PEN, having tyramine dihedral angles χ1 =−150° ± 30° and χ2=−155° ± 20°, had significant structural and conformational properties that were mutually compatible while respecting the PEO vector space. Comparison of these properties in the context of the divergent receptor selectivity of the studied opioid peptides suggests that the increased distortion of the peptide backbone in the closure region of c-PEN together with the pendant β,β-dimethyl group, combine to generate a steric volume which is absent in c-ORN and that may be incompatible with a restrictive topography of the μ receptor. The nature and stereo-chemistry of substituents adjacent to the closure region of the peptides could also modulate receptor selection by interacting with a charged (δ) or neutral (μ) subsite.

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Authors and Affiliations

  1. Laboratoire de Chimie Structurale, Département de Chimie, Faculté des Sciences, Université de Sherbrooke, J1K 2R1, Sherbrooke, Québec, Canada

    André Michel & Gérald Villeneuve

  2. The Biotechnology Research Institute of The National Research Council of Canada, 6100 RoyalMount Ave., H4P 2R2, Montréal, Québec, Canada

    John DiMaio

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  1. André Michel
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  2. Gérald Villeneuve
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  3. John DiMaio
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Michel, A., Villeneuve, G. & DiMaio, J. A proposal for the molecular basis of μ and δ opiate receptor differentiation based on modeling of two types of cyclic enkephalins and a narcotic alkaloid. J Computer-Aided Mol Des 5, 553–569 (1991). https://doi.org/10.1007/BF00135314

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  • DOI: https://doi.org/10.1007/BF00135314

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